Colonic orthostatic lavage is an iatrogenic phenomenon related to the administration of a purgative and therefore is predictable in its action and side effects. It is important to make the distinction between the use of iatrogenic purgation solutions and fluid/electrolyte replacement solutions used for treatment of vomiting and diarrhoea associated with gastroenteritis. The use of mainly hypotonic or isotonic solutions such as glucose-based ‘Bangladesh’ solution and rice-based solutions has been successful in patients with gastroenteritis and dehydration, a highly unpredictable disease. The physiological principle of coupled sodium and glucose transport in a 1:1 molar ratio in the intestine has been shown to be safe and effective.
Purgatives developed to date for orthostatic lavage to clean the bowel of faecal matter prior to colonoscopy have taken the form of either and isotonic, large volume lavage (e.g. Braintree's Golytely) or more hypertonic lavage products such as Fleet's sodium phosphate or sodium picosulfate (Picolax) products. The former generally cause little homeostatic disturbance or intra-vascular sodium and other electrolytes or fluid shifts because of their isotonic nature, which minimizes electrolyte absorption/secretion by the presence of high molecular weight polyethylene glycol (PEG mw 3350). However, these preparations have recently been reported to be associated with hyponatremia (Cohen D.C., et al., Lancet 357(9252): 282-283 (2001)). Products with sodium phosphate and sodium picosulfate are felt to be better tolerated (Fincher RK, et al., Am. J. Gastroenterol. 94(8): 2122-7 (1999)). However, these products have also been associated with a significant hypo-osmolar state and electrolyte imbalance, particularly hyponatremia. This, to a large extent, is contributed to by a loss of electrolytes through the resultant diarrhea caused by the lavage with concomitant replacement of this loss by water (without electrolytes) leading to hyponatremia and water intoxication associated with a hypo-osmolar state.
The symptoms of headache, lethargy and nausea reported by patients undergoing orthostatic lavage are felt to be due to an osmotic shift with resultant dilutional hyponatremia that is induced by the various bowel preparation products such as “Fleet”, Picolax etc. This effect appears to be more pronounced in adult females, perhaps as a result of relatively less total body water when compared to adult males and children (Fraser et al., Am. J. Physiol. 256: R880-5 (1989)).
The clinical features of hyponatremia (hypoosmolality) are highly variable and their severity correlates poorly with the level of serum sodium. Classically, the clinical features of severe hyponatremia are confusion, seizures and obtundation.
A decrease in plasma osmolality causes brain swelling (cerebral oedema) as water moves along osmotic gradients. In response, the brain loses solute from the intra- and extra-cellular fluid spaces, which returns brain water content back towards normal. Once the brain has equilibrated (i.e. volume-adapted) through solute losses, neurological features will be less prominent or resolve.
The rate of fall of serum osmolality is generally better correlated with morbidity and mortality than the actual magnitude of the decrease (Arieff, A. I. et al., Medicine (Baltimore) 55: 121-9 (1976)), and is somewhat arbitrarily defined as hypoosmolality developing over 24 to 48 hours. Mortality up to 50% has been reported in patients with acute hyponatremia (Arieff, A. I. et al., loc.cit.). Cerebral oedema develops when hypoosmolality exceeds the ability of the brain to regulate its volume by solute losses. In experimental models, acute hyponatremia results in the loss of sodium and chloride from the brain within 30 minutes, whilst potassium loss is more delayed. All electrolyte losses are maximal by 3 hours after initiation of hyponatremia (Melton, J. E. et al., Am. J. Physiol. 252: F661-9 (1987)).
Hence in some situations the effects of the various bowel purgative formulations currently available can lead to the unpleasant side effects of headache, malaise and dizziness and hypotension. Additionally, life threatening presentations of hypo-osmolar grand mal epileptic seizures, asphyxia and death have been reported.
Due to the accepted benefits of screening colonoscopic surveillance programs for the detection of colonic polyps and bowel cancer, the utilisation of colonic lavage is increasing rapidly. Indeed it is feasible that a large number of the population over the age of 50 years is likely to undergo colonoscopic examination. As a result, a considerable number of patients could potentially develop lavage-related hyponatremia and hypo-osmolar water intoxication with subsequent ‘dilution’ of other electrolytes leading to significant morbidity and potentially mortality.
Poor palatability leading to reduced patient compliance has been an important issue in the failure of some of the currently available products; either the volume is too large or the taste too objectionable for certain patients to comply with taking the prescribed bowel preparation. This leads to inadequate orthostatic lavage causing poor visibility at colonoscopy.
There is therefore a need for a purgative composition that reduces mortality and/or patient morbidity and/or which makes the procedure of purgation of the colon much more pleasant for the patient so as to facilitate patient compliance.
The present invention therefore provides novel electrolyte-enhanced purgatives which may be administered in relatively small liquid volumes, suitably in the form of a palatable soup mixture, but which may also be formulated in various other forms such as capsules, powders or compressed tablets. Thus, the compositions and purgatives of the present invention cause a purgative effect while ameliorating or overcoming the disadvantages associated with the administration of prior art purgatives, namely (a) symptoms associated with osmotic shifts and electrolyte imbalance; (b) hyponatremia; and (c) poor patient compliance owing to unpalatibility and/or the need to consume large volumes of liquid.